Melanoma: Diagnosis Melanoma - PDF of Slides.pdf · Benign Malignant Diameter • Melanoma is usually greater than 6 mm (the ... • Management of regional nodes in melanoma was controversial

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MelanomaDoreen M. Agnese, MD

Assistant ProfessorSurgical Oncology and Clinical Cancer Genetics

The Ohio State University

• 1 in 55 individuals will be diagnosed with melanoma over their lifetime

• 2008 estimates62,480 new cases8,420 deaths

Melanoma: Incidence and Mortality

SEER Cancer Statistics Review, 1975-2005, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2005/, based on November 2007 SEER data submission, posted to the SEER web site, 2008.

• Early diagnosis is key to improved outcomes

• ABCDE AsymmetryBorder irregularityColorDiameterEvolution

Melanoma: Diagnosis

Asymmetry• If you could fold the lesion in half, the 2

halves would not match.

Benign Malignant

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Border• Melanoma often has uneven or blurred

borders

Benign Malignant

Color• Melanoma contains mixed shades of tan,

brown and black; it can show traces of red, blue or white

Benign Malignant

Diameter• Melanoma is usually greater than 6 mm (the

size of a pencil eraser)

Benign Malignant

• Changes in appearance, such as spreading of pigment into surrounding skin

• A mole that looks scaly, oozes or bleeds• Itching, tenderness or pain in a mole• Brown or black streak under a nail• Bruise on the foot that does not heal

Evolution and other suspicious signs

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Melanoma: Diagnosis• Excisional biopsy (elliptical, punch, or

saucerization): 1-3 mm margin, avoid larger margin to permit accurate lymphatic mapping

• Full thickness incisional or punch: attempt to perform in clinically thickest portion of lesion

Melanoma: Diagnosis• Avoid shave biopsy: may compromise

pathologic diagnosis and complete assessment of thickness

• Path report should include depth of invasion in mm, Clark’s level, presence or absence of ulceration, mitotic count, and status of peripheral and deep margin

Melanoma: Survival & Stage• Stage Distribution at

Diagnosis

Localized: 81%

Regional: 12%

Metastatic: 4%

Unstaged: 4%

• 5-year Survival rates

98.7%

65.1%

15.5%

77.4%

SEER Cancer Statistics Review, 1975-2005, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2005/, based on November 2007 SEER data submission, posted to the SEER web site, 2008.

• Complete history and physical exam, including complete skin exam and nodal exam

• Assessment of risk factorsFamily historyPrevious melanomaHistory of dysplastic nevi/atypical molesTanning bed, peeling sunburns < 18

Work-up of newly diagnosed patient

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Melanoma: Surgical Care

• Excision of the primary lesion

• Nodal assessment

Surgical MarginsTumor Thickness

In situ≤ 1 mm1.01 – 2 mm2.01 – 4 mm> 4 mm

Recommended margin0.5 cm1 cm1 – 2 cm2 cm2 cm

Guidelines for Nodal Assessment

• For tumors ≥ 1 mm, sentinel lymph node biopsy (SLN)

• For tumors < 1 mm, no SLNconsider if young age or high risk histology (ulceration, mitotic rate > 1/mm2, Clark’s level IV)

• For any positive nodes, complete lymph node dissection

History of Nodal Assessment

• Management of regional nodes in melanoma was controversial for many years

• Some favored elective node dissection, but morbid procedure and only 20% of individuals with intermediate thickness lesions have positive nodes

• For many, drainage pattern uncertain

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• Introduced by Morton in 1990• Dual injection technique

Technetium sulfur colloidLymphazurin/Isosulfan blue dye

• Lymphoscintigraphy• Small incisions to remove nodes that are

hot, blue, or clinically suspicious

Sentinel lymph node biopsy technique

Lymphoscintigraphy

Sentinel Lymph Node

Melanoma Sentinel Lymph Node Trial 1

N Engl J Med 2006; 355: 1307-17

533 814

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N Engl J Med 2006; 355: 1307-17

Cases

Excision Alone

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Locally advanced, clinically node negative

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Locally advanced, clinically node negative, sentinel node positive

Locally advanced, clinically node negative, sentinel node positive

• Stage 0 (in situ)At least annual skin exam for lifeMonthly self skin exam

• Stage IA (thin, node neg, no ulceration)H&P with emphasis on skin and nodes every 3-12 months for 5 years, then annually for lifeMonthly self skin exam

Follow-up

• Stage IB-IV, NEDH&P with emphasis on skin and nodes every 3-6 mos for 2 years, then every 3-12 mos for 2 years, then annuallyCXR, LDH, CBC annually (optional)CT scans for symptoms, can be considered routinely for follow-up in higher stagesMonthly self skin exam and node exam

Follow-up

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Surgery for Metastatic Disease

• Palliative procedures may be performed for relief of symptoms

• Predictors of success for metastectomywith curative intent:

Site of metastasis (skin, soft tissue, nodes>pulmonary>visceral)Number of metastatic lesionsDisease-free interval

Ann Surg Oncol 2002; 9(8): 762-770

• JWCI/SMU study:5-yr survival of 29% in patients undergoing complete resection of liver mets26204 patients with melanoma• 1750 (7%) with liver mets

–Resection attempted in 34 (2%)»Complete resection only possible in 18 »5 patients (0.3%) experienced long-term

disease-free survival

Surgery for Metastatic Disease-patient selection!

Arch Surg 2001; 136:950-955

MelanomaKari Kendra MD, PhD

Assistant Professor of MedicineThe Ohio State University

Case 134 y/o female presented with a bleeding mole

on her arm.

• Biopsy: nodular melanoma, 4.1 mm deep, with ulceration, mitotic rate 15/10 HPF

• Wide excision: no residual tumor

• Sentinel Node: positive for 2/2 LN

• Axillary LN dissection: 0/20 LN

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Case 1

What is the next step?

Prognostic Indicators• Thickness (Breslow depth)

• Nodal status

• Ulceration

• Satellite lesions

• In transit lesions

Case 1Our 34 y/o female has multiple poor

prognostic indicators:

• Depth > 1.0 mm

• Lymph nodes positive

• Ulceration present

• Mitotic rate high

Copyright © American Society of Clinical Oncology

Balch, C. M. et al. J Clin Oncol; 19:3635-3648 2001

Fifteen-year survival curves comparing localized melanoma (stages I and II), regional metastases (stage III), and distant metastases (stage IV)

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Adjuvant therapy for high risk patients

• What therapies are available?

• How do we identify patients for treatment?

Systemic Therapy:Adjuvant

• Biologic AgentsIFNGM-CSF

• Chemotherapeutic agentsCisplatin, Vinblastine, DTIC (CVD)Cisplatin, Vinblastine, DTIC, IL2, IFN (Biochemotherapy)

Adjuvant Therapy with Interferon Alfa-2b

(E1684)

FDA approved • IFN-alpha 2b for adjuvant treatment of melanoma

patients with thick primary tumors (> 4mm) or resected nodal disease

• Positive response data is for node + patients only


(E1684)• Patient population

Breslows depth >4mmLN+ after ELNDClinical LN+ with synchronous primaryRegional LN recurrence after surgery for primary

Kirkwood et al, JCO 1996;14:7

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(E1684)

Treatment• High-dose IFNα-2b : 20 MU/m2 IV, 5 days per

week for 4 weeks (induction phase) followed by 10 MU/m2 SC TIW for 48 weeks (maintenance)

• Observation

IFNα-2b Observationmedian DFS 1.7 yr 1.0 yr

OS 3.8 yr 2.8 yr

* benefit greatest in LN+ patients


(E1684)


(E1684)• TOXICITIES:

ConstitutionalMyelosuppressionHepatotoxocityNeurologic

* 67% of all patients had severe (grade 3) toxicity at some point during treatment

* Supportive care is necessary


(E1684)IFNα-2b Observation

median DFS 1.7 yr 1.0 yr

OS 3.8 yr 2.8 yr

* benefit greatest in LN+ patients

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Adjuvant Therapy with Interferon α-2b

(E1690)Treatment:

1. High-dose IFNα-2b

2. Low dose IFNα-2b

3. Observation


(E1690)• Patient population:

T4cN0 T1-4cN0pN1T1-4cN1Recurrent LN+

* Lymphadenectomy not requiredKirkwood et at, JCO 2000;18:2444

• High-dose IFNα-2b : 20 MU/m2 IV, 5 days per week for 4 weeks (induction phase) followed by 10 MU/m2 SC TIW for 48 weeks

• Low dose IFNα-2b: 3 MU/m2 SC TIW - maintenance phase for 2 years

• Observation


(E1690)

RESULTS (642 patients)

• Relapsed free survival HD > observation• Overall survival HD = LD = observation* Post relapse survival effected by salvage

therapy?


(E1690)

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Adjuvant Therapy with GM-CSF

• Patient population: Stage III ( >4 positive LN or nodal mass > 3 cm)

Stage IV

* All rendered clinically disease-free by surgery before enrollment

*Spitler et al, JCO 2000;18:1614


• Treatment:GM-CSF 125 mcg/m2 sc days 1-14followed by 14 days of rest

Duration - 1 year


GM-CSF ObservationMedian survival 37.5 mos 12.2 mos1 yr 89% 45%2 yr 64% 15%

* Well tolerated* Phase 3 data is pending

Adjuvant Therapy with Interferon

Currently recommended for:1. Ulcerated primary lesions of any depth

with or without a positive sentinel node

2. Positive lymph nodes

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Case 134 y/0 female presented with a bleeding mole

on her arm. • Biopsy: nodular melanoma, 4.1 mm deep,

with ulceration, mitotic rate 15/10 HPF• Wide excision: no residual tumor• Sentinel Node: positive for 2/2 LN• Axillary LN dissection: 0/20 LN

Case 1:Current Options

• IFN (1 yr of therapy)

• Observation

• Clinical trial

Clinical Trials

• CALGB 500103: Phase III Randomized Study of Four Weeks High Dose IFN-alpha 2b in Stage T3-T4 or N1 (microscopic) Melanoma

• OSU 07033: A Pilot Study of IFN-alpha-2b Dose Reduction with Dose Optimization

Metastatic Disease

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Case 220 y/o male:

• Presents with SOB, CT: bilateral pulmonary nodules and axillary mass

• Biopsy of axillary mass: melanoma

What is his prognosis?

What treatments are available?




Metastasis

• Most frequent first distant sites include:Skin Subcutaneous tissues Distant lymph nodes

• Surveillance is important

Metastatic Melanoma: Treatment

Localized• Surgery – isolated metastases, limited in size and number, rendered disease free

• Radiation – CNS mets, cord compression, pain control

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Metastatic Melanoma

Surgery:

• Isolated metastases

• Limited in size and number

• Rendered disease free

Prognosis: MetastaticMelanoma

Single institution data (John Wayne Institute)(548 patients)

• Site of metastasisSkin/sc nodule (median survival 11 months)GI (median survival 6 months)Liver, bone, or brain (median survival 2 – 4 months)

(Essner R, 2001, Fifth World Conference on Melanoma)

Prognosis: MetastaticMelanoma

Resection can improve median survival with resection without resection

(months) (months)Skin/sc nodules 24 11GI 49 6Brain 9 2 - 4

(Essner R, 2001, Fifth World Conference on Melanoma)

Radiation Therapy

• CNS metastases

• Vertebral metastases with cord compression

• Pain control

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Case 220 y/o male:



What is his prognosis?


Metastatic MelanomaSystemic therapy:

• Chemotherapy – directly target the tumor

• Immunotherapy –activates the immune system to recognize and destroy the cancer

Biologic Therapy:HD IL2

• Cycle: 600,000 IU/kg every 8 hours x 14 doses, repeated after 6 – 9 days of rest

RR 16%

CR 6%, PR 10%

• Median response duration for CR, not reached 6 years after completion of the study

• 28% of responding patients remained disease free

Atkins et al, JCO 1999

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Biologic Therapy:IFN α

• RR 10 – 24%• Dose:

10 MU/m2 TIW 20 MU/m2 QD x 5 /week

• Delayed responses observedInitial progression, CR at 12 months

(Kirkwood et at, Ann Int Med 1985)

Biologic Therapy(IL2, IFN)

• Potential benefits:Durable responses

• Limitations:Toxicity

Case 220 y/o male:



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Response Rate

• DTIC 20%• Vindesine 14%• Vinblastine 13%• Carmustine 18%• Taxanes 18%• Cisplatin 23%• Temozolamide 20%

Chemotherapy:Single Agents

Best studied:

Dacarbazine (DTIC)• RR 10% – 20%

• Responders survive longer than nonresponders

• Responses most frequent in skin, subcutaneous tissue, lymph node, and lung metastases

Chemotherapy:Single Agents

Single Agent: DTIC

RR 20%• Median duration of response is 5 – 6

months• CR 5% (phase III trials with 580 pt)• CR predominantly in sc nodules and lymph

node metastases• Liver, bone, and brain, respond

infrequently

Single Agent:Temozolamide

• Active metabolite of DTIC• Phase II studies show similar RR to DTIC• Oral• Dose: 150 mg/m2/d, D 1 – 5, q 28 days• CNS penetration

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Chemotherapy:Combination Regimens• Dartmouth regimen

DTIC, BCNU, cisplatin, tamoxifen• CVD

Cisplatin, vinblastine, dacarbazine• CVT

Cisplatin, vinblastine, temodar• Taxol/carboplatin

Combination chemotherapy:Paclitaxel and carboplatin

N = 31 patients• 2 previous therapies, incuding temodar or DTIC• Taxol 100 mg/m2, carboplatin AUC 2

On day 1, 8, and 15 of a 28 day cycle• 26% PR, 19% SD = clinical benefit of 45%

• Median TTP 3 months, median OS of 7.9 months • In responders median OS = 5.7 months

Chemotherapy:• Single agents:

DacarbazineTemodar

• Combination agents:CVDTaxol/carboplatin

Biologic Therapy:

• Interleukin 2

• Interferon

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Case 2

20 y/o male:



Case 2


◦ Immunotherapy with Interleukin 2

◦ Chemotherapy with dacarbazine

◦ Clinical trial

Clinical Trials

• OSU 0132: A Phase 2 Study of Bevacizumab and Interferon-alpha-2b in Metastatic Malignant Melanoma

• OSU 04105: A Phase I Study of PS-341 (Brtezomib, Velcade) and Interferon-alpha-2b in Malignant Melanoma

Clinical Trials• OSU 06006: A Phase I Study of Bolus High Dose

IL2 with Sorafenib in Patients with Unresectableor Metastatic Melanoma

• OSU 07137: A Phase I, Open-label, dose escalation study of ANA773 Tosylate, an Oral Prodrug of a Toll-Like Receptor-7 Agonist, in Patients with Advanced Cancer

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• OSU 08054: A Randomized, Double-blind, Phase 3 Trial of STA-4783 in Combination with Paclitaxelversus Paclitaxel Alone for Treatment of Chemotherapy-Naïve Subjects with Stage IV Metastatic Melanoma (SYMMETRY)

• OSU 08059: A Phase II Trial of Intravenous Administration of Reovirus Serotype 3 - Dearing Strain (Reolysin®) in Patients with MetastaticMelanoma.

Clinical Trials(opening soon)

MODIFY RISK!!!• Risk behaviors

>3 sunburnsEpisodic excessive sunlight exposureLong term continuous sunlight exposureUV exposure at tanning salons

Early Detection!




Documents

Melanoma: Diagnosis Melanoma - PDF of Slides.pdf · Benign Malignant Diameter • Melanoma is usually greater than 6 mm (the ... • Management of regional nodes in melanoma was controversial